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EP2804852A2 - Composés thérapeutiques - Google Patents

Composés thérapeutiques

Info

Publication number
EP2804852A2
EP2804852A2 EP13701897.4A EP13701897A EP2804852A2 EP 2804852 A2 EP2804852 A2 EP 2804852A2 EP 13701897 A EP13701897 A EP 13701897A EP 2804852 A2 EP2804852 A2 EP 2804852A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
aryl
phenyl
halo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13701897.4A
Other languages
German (de)
English (en)
Inventor
Venkatram R. Mereddy
Lester R. Drewes
Mohammad Abrar ALAM
Sravan K. JONNALAGADDA
Shirisha GURRAPU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Minnesota Twin Cities
University of Minnesota System
Original Assignee
University of Minnesota Twin Cities
University of Minnesota System
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Minnesota Twin Cities, University of Minnesota System filed Critical University of Minnesota Twin Cities
Publication of EP2804852A2 publication Critical patent/EP2804852A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/63—Carboxylic acid nitriles containing cyano groups and nitrogen atoms further bound to other hetero atoms, other than oxygen atoms of nitro or nitroso groups, bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Definitions

  • MCTs Monocarboxylate Transporters
  • SLC16 solute carrier 16
  • Malignant tumors contain aerobic and hypoxic regions and intratumoral hypoxia increases the risk of cancer advancement, and metastasis. Tumor hypoxia leads to treatment failure, relapse and patient mortality as these cells are generally resistant to standard chemo- and radiation therapy. In regions of hypoxia, cancer cells metabolize glucose into lactate, whereas nearby aerobic cancer cells take up this lactate via the mono-carboxylate transporter 1 (MCT1) for oxidative phosphorylation. MCT1 expression is elevated in an array of human tumors including brain, breast, head, neck, lung and colon.
  • MCT1 mono-carboxylate transporter 1
  • cancer cells Under hypoxic conditions, cancer cells upregulate glucose transporters and consume large quantities of glucose. Cancer cells also upregulate glycolytic enzymes and convert glucose into lactate, which is then effluxed out of the cell via MCT4. The nearby aerobic cancer cells take up this lactate via the MCT1 for energy generation through oxidative phosphorylation. Thus, the limited glucose available to the tumor is used most efficiently via a synergistic metabolic symbiosis. This utilization of lactate as an energy substitute for survival prevents the aerobic cells from consuming large quantities of glucose. Targeted inhibition of MCT4 will lead to lactic acidosis and consequent death of hypoxic cells, while MCT1 inhibition will cause aerobic cancer cells to consume glucose instead of lactate, thus resulting in further stress and death of hypoxic cancer cells.
  • MCT1 may also be useful for treating autoimmune diseases and preventing organ transplant rejection.
  • the rate of short term graft survival has been improved by current immunosuppressants, however in the past two decades there has been no
  • agents that are useful for treating or preventing cancer or that are useful for treating or preventing autoimmune diseases or that are useful for preventing transplant rejection There is also a need for agents that are useful for diagnosing cancer or autoimmune diseases or for imaging cancerous cells or cells involved in an autoimmune response.
  • the invention provides a compound of the invention which is a compound of formula I:
  • X is CN, Y is R 5 and the dashed bond is absent;
  • R 1 is H or (C r C 6 )alkyl
  • R 2 is H, (Ci-C 6 )alkyl, (C,-C 6 )alkoxy, halo(C C 6 )alkyl,
  • R 3 is H, (Ci-C 6 )alkyl, (d-C 6 )alkoxy, halo(d-C 6 )alkyl,
  • R 4 is H, (d-C 6 )alkyl, (d-C 6 )alkoxy, halo(C,-C 6 )alkyl,
  • R 5 is H, (C ! -C 6 )alkyl, (d-C 6 )alkoxy, halo(C ! -C 6 )alkyl,
  • R 6a and R 6b are each independently H, (d-C 7 )alkyl, (C 2 -C 7 )alkenyl, (C 2 -C 7 )alkynyl, aryl(d-C )alkyl-, heteroaryl(Ci-C6)alkyl-, heterocycle(C 1 -C )alkyl-, aryl, heterocycle or heteroaryl, wherein any (C]-C 7 )alkyl, (C 2 -C 7 )alkenyl, (C 2 -C 7 )alkynyl, aryl(d-C 6 )alkyl-, heteroaryl(d-C )alkyl-, heterocycle(C 1 -C 6 )alkyl-, aryl, heterocycle or heteroaryl of R 6a and R 6b is optionally substituted with one or more (e.g.
  • R 6a and R 6b together with the nitrogen to which they are attached form a heterocycle, wherein the heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; each R a is independently H, (Ci-C 6 )alkyl, aryl(Ci-C 6 )alkyl- or aryl;
  • each 3 ⁇ 4 is independently (C 1 -C )alkyl, aryl(C 1 -C 6 )alkyl- or aryl;
  • R c and R d are each independently H, (C]-C 6 )alkyl, aryl(C!-C6)alkyl- or aryl; or Rg and R d together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • each Z 1 is independently (Ci-C )alkyl, (C];-C 6 )alkoxy, halo(C ! -C 6 ) lkyl,
  • each Re is independently H, (Q-C ⁇ alkyl, aryl(C 1 -C 6 )alkyl- or aryl;
  • each R f is independently (CrC 6 )alkyl, aryl(C)-C )alkyl- or aryl;
  • R g and R h are each independently H, (C 1 -C 6 )alkyl, aryl(CrC 6 )alkyl- or aryl; or R g and R h together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a method for inhibiting cancer (e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck) cell growth comprising contacting the cancer cell in vitro or in vivo with an effective amount of a compound of formula I, or a salt thereof.
  • cancer e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck
  • the invention also provides a method for treating cancer (e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer) in a mammal (e.g. a human) comprising administering to the mammal an effective amount of compound as described in formula I, or a pharmaceutically acceptable salt thereof.
  • cancer e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer
  • a mammal e.g. a human
  • the invention also provides a method for treating an autoimmune disease (e.g.
  • a mammal e.g. a human
  • administering comprising administering to the mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method for preventing transplant rejection (e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection) or tissue graft rejection (e.g. bone, tendon, cornea, skin, heart valve and vein) in a mammal (e.g. a human) comprising administering to the mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • transplant rejection e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection
  • tissue graft rejection e.g. bone, tendon, cornea, skin, heart valve and vein
  • the invention also provides a method for diagnosing cancer (e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer) or for diagnosing an autoimmune disease (e.g. rheumatoid arthritis) in a mammal comprising administering to the mammal (e.g. a human) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof and measuring or imaging the fluorescence of the compound of formula I wherein the fluorescence correlates with cancer or an autoimmune disease.
  • cancer e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer
  • an autoimmune disease e.g. rheumatoid arthritis
  • the invention also provides a method for imaging cancerous cells (e.g. brain, breast, head, neck, lung or colon cancer cells) or for imaging cells involved in an autoimmune response (e.g. rheumatoid arthritis) or for imaging cells involved in transplant rejection (e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection) or tissue graft rejection (e.g. bone, tendon, cornea, skin, heart valve and vein) comprising contacting the cells in vivo or in vitro with a compound of formula I, or a salt thereof and imaging the fluorescence of the compound of formula I while in contact with the cell.
  • cancerous cells e.g. brain, breast, head, neck, lung or colon cancer cells
  • an autoimmune response e.g. rheumatoid arthritis
  • transplant rejection e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection
  • tissue graft rejection e
  • the invention also provides a method for altering brain function (e.g. long-term memory formation) in a mammal (e.g. a human) comprising administering to the mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • a mammal e.g. a human
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in medical therapy.
  • the invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of cancer (e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer) in a mammal (e.g. a human).
  • cancer e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer
  • a mammal e.g. a human
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of cancer (e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer).
  • cancer e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer.
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic alteration of brain function
  • the invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of an autoimmune disease (e.g. rheumatoid arthritis) in a mammal (e.g. a human).
  • an autoimmune disease e.g. rheumatoid arthritis
  • a mammal e.g. a human
  • the invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for altering brain function (e.g. long-term memory formation) in a mammal (e.g. a human).
  • a mammal e.g. a human
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an autoimmune disease (e.g. rheumatoid arthritis).
  • the invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for preventing transplant rejection (e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection) or tissue graft rejection (e.g. bone, tendon, cornea, skin, heart valve and vein) in a mammal (e.g. a human).
  • transplant rejection e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection
  • tissue graft rejection e.g. bone, tendon, cornea, skin, heart valve and vein
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the prevention of transplant rejection (e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection) or tissue graft rejection (e.g. bone, tendon, cornea, skin, heart valve and vein).
  • transplant rejection e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection
  • tissue graft rejection e.g. bone, tendon, cornea, skin, heart valve and vein.
  • the invention also provides a compound of formula I, or a salt thereof for use in diagnosing cancer (e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck) or for diagnosing a autoimmune disease (e.g. rheumatoid arthritis).
  • cancer e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck
  • a autoimmune disease e.g. rheumatoid arthritis
  • the invention also provides a compound of formula I, or a salt thereof for use in imaging cancerous cells (e.g. brain, breast, head, neck, lung or colon cancer cells) or for imaging cells involved in an autoimmune response (e.g. rheumatoid arthritis) or for imaging cells involved in transplant rejection (e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection) or tissue graft rejection (e.g. bone, tendon, cornea, skin, heart valve and vein).
  • cancerous cells e.g. brain, breast, head, neck, lung or colon cancer cells
  • an autoimmune response e.g. rheumatoid arthritis
  • transplant rejection e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus transplant rejection
  • tissue graft rejection e.g. bone, tendon, cornea, skin, heart valve and vein.
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof.
  • Figure 1 illustrates the anti-cancer effect of Compound 20, and Compound 14 on the tumor growth in WiDr xenograft tumor model from Example 7.
  • Figure 2 illustrates the anti-cancer effect of Compound 20, and Compound 14 on the tumor growth in WiDr xenograft tumor model from Example 7.
  • Figure 3 illustrates the Anti-Cancer Effect of Compound 20 on the Tumor Growth in the WiDr xenograft tumor model (after 14 Days) from Example 8.
  • Figure 4 illustrates the anti-cancer effect of Compound 20 on the tumor growth in the WiDr xenograft tumor model (after 22 Days) from Example 8.
  • Figure 5 illustrates the anti-cancer effect of Compound 20 on the tumor weight in the WiDr xenograft tumor model from Example 8.
  • Figure 6 illustrates the body weight changes in mice from Example 8. Detailed Description
  • halo or halogen as used herein refers to fluoro, chloro, bromo, or iodo.
  • alkyl refers to straight and branched hydrocarbon groups
  • alkenyl refers to straight or branched hydrocarbon groups containing at least one carbon-carbon double bond
  • alkynyl refers to straight or branched hydrocarbon groups containing at least one carbon-carbon triple bond
  • alkoxy refers to groups of the formula alkyl-O-, where alkyl is as defined herein.
  • Reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • haloalkyl refers to an alkyl as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent.
  • a halo (C 1 -C 6 )alkyl is a (C 1 -C )alkyl wherein one or more of the hydrogen atoms have been replaced by a halo substituent.
  • Such a range includes one halo substituent on the alkyl group to complete halogenation of the alkyl group.
  • aryl refers to a single aromatic ring or a multiple condensed ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic. Such multiple condensed ring systems may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system.
  • Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
  • heteroaryl refers to a single aromatic ring or a multiple condensed ring system.
  • the term includes single aromatic rings of from about 1 to 6 carbon atoms and about 1 -4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings.
  • the sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
  • Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
  • the term also includes multiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more heteroaryls (e.g.
  • naphthyridinyl naphthyridinyl
  • heterocycles e.g. 1 , 2, 3, 4- tetrahydronaphthyridinyl
  • carbocycles e.g. 5,6,7,8-tetrahydroquinolyl
  • aryls e.g. indazolyl
  • Such multiple condensed ring systems may be optionally substituted with one or more (e.g. 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring.
  • the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e.g. a nitrogen).
  • heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.
  • heterocyclyl refers to a single saturated or partially unsaturated ring or a multiple condensed ring system.
  • the term includes single saturated or partially unsaturated rings (e.g. 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the ring may be substituted with one or more (e.g. 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
  • Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl.
  • heterocycle also includes multiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more heterocycles (e.g. decahydronapthyridinyl ), carbocycles (e.g. decahydroquinolyl) or aryls.
  • heterocycles e.g. decahydronapthyridinyl
  • carbocycles e.g. decahydroquinolyl
  • aryls aryls.
  • the rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • the point of attachment of a multiple condensed ring system can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. It is also to be understood that the point of attachment for a heterocycle or heterocycle multiple condensed ring system can be at any suitable atom of the heterocycle or heterocycle multiple condensed ring system including a carbon atom and a heteroatom (e.g. a nitrogen).
  • heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomo holinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1 ,2-dihydropyridinyl, 2,3- dihydrobenzofuranyl, 1 ,3-benzodioxolyl and 1 ,4-benzodioxanyl.
  • carbocycle refers to a single saturated (i.e., cycloalkyl) or a single partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 8 carbon atoms (i.e. (C 3 -C 8 )carbocycle).
  • carbocycle or “carbocyclyl” also includes multiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles having 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g. spiropentane, spiro[4,5]decane, spiro[4.5]decane, etc), via two adjacent carbon atoms to form a fused connection such as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system (e.g. decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g.
  • the "carbocycle” or “carbocyclyl” can also be optionally substituted with one or more (e.g. 1 , 2 or 3) oxo groups.
  • monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-l-enyl, l-cyclohex-2-enyl and l-cyclohex-3-enyl.
  • a specific group of compounds of formula I are compounds of formula lb:
  • (Ci-C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl or hexyl;
  • (Ci-C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • (C 2 -C 6 )alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C 2 -C )alky
  • a specific value for R 1 is H.
  • a specific value for R is H or methoxy.
  • R 2 Another specific value for R 2 is methoxy.
  • R 2 Another specific value for R 2 is H.
  • a specific value for R is H.
  • a specific value for each of R 6a and R 6b independently is (C 1 -C 6 )alkyl, (C2-C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl(C 1 -C 6 )alkyl-, aryl or heterocycle, wherein any (Ci-C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl(C r C 6 )alkyl-, aryl or heterocycle of R 6a and R 6b is optionally substituted with one or more Z 1 groups; or R 6a and R 6b together with the nitrogen to which they are attached form a heterocycle optionally substituted with one or more Z 1 groups.
  • R 6a and R 6b independently is (Ci- C 6 )alkyl, aryl(C 1 -C 6 )alkyl- or aryl, wherein any (C r C 6 )alkyl, aryl(C C 6 )alkyl- or aryl of R 6a and R 6 is optionally substituted with one or more Z 1 groups.
  • a s ecific value for -NR 6a R 6b is:
  • a specific compound of formula I is:
  • Another specific compound of formula I is:
  • the compounds of formula I do not include: (E)-2-cyano-3 -(4-(dipropylamino)phenyl)acrylic acid,
  • the compounds of formula I do not include: 7-(dimethylamino)-2-oxo-2H-chromene-3 -carboxylic acid,
  • the compounds of formula I do not include: (E)-2-cyano-3 -(4-(dipropylamino)phenyl)acrylic acid,
  • the compounds of formula I do not include: (E)-2-cyano-3 -(4-(diethylamino)-2-methoxypheny l)acrylic acid.
  • Schemes 1-3 Processes for preparing compounds of formula I are provided as further embodiments of the invention and are illustrated in Schemes 1-3 in which the meanings of the generic radicals are as given above unless otherwise qualified.
  • Scheme 1 depicts a general procedure for the synthesis of 2-cyano-phenyl acrylic acid compounds of formula I
  • Scheme 2 depicts a general procedure for the synthesis of methoxy substituted 2-cyano-phenyl acrylic acid compounds of formula I
  • Scheme 3 depicts a general procedure for the synthesis of 2-oxo-2H-chromene-3- carboxylic acid compounds of formula I.
  • An intermediate useful for preparing a compound of formula I is a compound of the formula la, 2a or 3a or a salt thereof.
  • a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a- ketoglutarate, and a-glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • MCT's e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck.
  • compounds and compositions described herein may be useful to prevent organ (e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus) transplant rejection as well as tissues graft (e.g. bone, tendon, cornea, skin, heart valves, and veins) rejection.
  • organ e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus
  • tissues graft e.g. bone, tendon, cornea, skin, heart valves, and veins
  • autoimmune diseases e.g. rheumatoid arthritis
  • Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other agents that are useful for the treatment of cancer (e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer) or autoimmune diseases (e.g. rheumatoid arthritis) or agents that are useful for preventing transplant rejection such as organ transplant (e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus) rejection and or tissue graft (e.g. bone, tendon, cornea, skin, heart valve, and vein) rejection.
  • cancer e.g. lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head and neck cancer
  • autoimmune diseases e.g. rheumatoid arthritis
  • transplant rejection e.g. transplant rejection
  • organ transplant e.g. heart, kidney, eye, liver, lung, pancreas, intestine, and thymus
  • the invention also provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula I or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat cancer or an autoimmune disease or to prevent transplant rejection.
  • the ability of a compound of the invention to inhibit MCT1 may be determined using pharmacological models which are well known to the art, or using Test A described below.
  • Test A MCT1 Inhibition via Lactate Uptake Rat Brain Endothelial Cells
  • the entire lactate uptake studies for the inhibition of MCT1 were carried out on RBE4 (Rat Brain Endothelial 4) cells.
  • the expression of MCT1 on these cells was confirmed by Western Blotting.
  • the cells were plated approximately 20-24 hours before the experiment, the number of cells being approximately 10 5 cells per well.
  • the test compounds were dissolved in DMSO and diluted 1000 times using a solution of HEPES buffer (pH 7.43) which consists of 3 ⁇ 14 C-Lactate and 2 ⁇ L-Lactate.
  • the cells were washed twice with 500 ⁇ of HEPES buffer and the cells were allowed to equilibrate for 15 minutes at 37 °C.
  • the HEPES buffer was removed and 250 ⁇ of the test sample was added in triplicates.
  • compounds of the invention may be useful as therapeutic agents for the treatment of cancer (lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head or neck cancer) or autoimmune diseases (e.g. rheumatoid arthritis) or for preventing transplant rejection (e.g. heart, kidney, eye, liver, lung, pancreas, intestine, or thymus transplant rejection) or for preventing tissue graft rejection (e.g. bone, tendon, cornea, skin, heart valve or vein graft rejection).
  • cancer lung, breast, brain, prostate, pancreatic, colorectal, ovarian, head or neck cancer
  • autoimmune diseases e.g. rheumatoid arthritis
  • transplant rejection e.g. heart, kidney, eye, liver, lung, pancreas, intestine, or thymus transplant rejection
  • tissue graft rejection e.g. bone, tendon, cornea, skin, heart valve or vein graft rejection.
  • Compounds of the inventions may also be useful for diagnosing cancer or cells involved in autoimmune diseases or transplant rejection or tissue graft rejection.
  • the coumarin compounds described herein exhibit fluorescence of excitation -350 nm and emission ⁇ 450nm. Since rapidly growing cells such as cancer cells and T cells uptake these compounds more than normal cells, the fluorescent MCT1 inhibitors described herein may be useful for imaging cancerous cells or cells involved in an autoimmune response. Additionally, compounds of the invention may be useful as pharmacological tools for the further investigation of cancer function or for the processes involved in an autoimmune response.
  • mice weighing -27 grams were randomly assigned into 5 groups (12 animals, 6 male and 6 female per group), one group being the control group without any drug administration (food only).
  • the drugs were administered twice daily by P.O. or I.P..
  • Group 1 and 3 were administered orally with 50mg/Kg of Compound 20 and 18mg/Kg of Compound 14 respectively.
  • Group 2 and 4 mice were injected intraperitoneally with 6.67mg/Kg of Compound 20 and 5.3mg/Kg of Compound 14 (dissolved in water) respectively.
  • the body weights of mice were recorded daily for 22 days. At the end of the 22 nd day, 3 mice were randomly selected from each group and their blood samples were collected for detailed analysis of white blood cell
  • mice were then euthanized with C0 2 .
  • mice Female BALB/c nude mice weighing ⁇ 20g were taken and 5.0 10 6 WiDr cancer cells were implanted into their right flanks with a 1 :1 mixture of O.lmL PBS and matrigel. The tumor was allowed to grow to a size of -150 cubic millimeters (14 days). The mice were randomly chosen by chance and assigned into 5 groups (6 mice per group), one group being the control group to which tumor was allowed to grow without any drug administration (food only). The drugs were administered twice daily by P.O. or LP.. Group 1 mice were administered orally with 50 mg/kg of Compound 20. Groups 2, 3 and 4 mice were treated via IP with 10 mg/kg
  • Compound 20 8 mg /kg of Compound 14 and 238mg/kg CHC respectively. Body weight changes were recorded every two days for 3 weeks.
  • MCT1 inhibitors do not cause systemic toxicity and are well tolerated in nude mice.
  • mice 60 male ICR mice were split into two groups of 30. In each group the mice were prescribed Compound 20 at a dosage of lOOmg/kg. This dose was administered orally in group 1 and intraperitoneally in group 2. Each group of 30 mice was subdivided into groups of 3 mice. Blood samples were taken through orbital sinus method at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administering Compound 20 and taken into tubes with anticoagulant at room temperature at least 30 minutes prior to centrifugation, then centrifuged at 10000 rpm for 5 minutes at 4 °C to separate plasma from the blood samples. Following centrifugation, the resulting serum was transferred to clean tubes and stored frozen at -80 °C.
  • mice Immediately following the blood samples, the brain tissue samples of mice were removed and stored frozen at -80 °C. A 20% brain homogenate was prepared by weighing brain tissue sample and adding, corresponding volume of saline into the manual homogenator. The dilution factor was 5
  • Plasma and Brain samples were centrifuged at 15777xg for 5 minutes, and 180ul of supernatant was placed in a 96-well assay plate. To each well, 200ul of a 50% ACN/H 2 0 was added and the plates were shake-mixed for 3 minutes. 5ul aliquots of each well were then analyzed using LC- MS/MS.
  • the Area Under the curve value from time 0 to 24 hours was defined as AUC t- >iast and calculated using the linear trapezoidal rule.
  • Table 4 illustrates the individual and mean plasma concentration data (ng/mL) for Compound 20 after intragastrical administration to mice.
  • Table 5 illustrates individual and mean plasma concentration data (ng/mL) for Compound 20 after intraperitoneal administration to mice.
  • Table 6 illustrates mean pharmacokinetic parameters of Compound 20 in mice
  • AUC 0 .iast ar ea under the plasma concentration-time curve from time zero to time of last measurable concentration
  • AUC 0- ⁇ is area under the plasma concentration-time curve from time zero to infinity
  • T max is time to reach maximum (peak) plasma concentration following drug administration
  • /2 is biological half-life of the drug
  • Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration
  • CLz/F is apparent total body clearance of the drug from plasma
  • C max maximum (peak) plasma drug concentration.
  • mice Female BALB/c nude mice weighing ⁇ 20g were taken and 5.0 10 6 WiDr cancer cells were implanted into their right flanks with a 1 : 1 mixture of 0.1 mL PBS and matrigel. The tumor was allowed to grow to a size of -150 cubic millimeters (2 weeks). The mice were randomly chosen by chance and assigned into 5 groups (6 animals/group), one group being the control group to which tumor was allowed to grow without any drug administration (food only). The drugs were administered twice daily by P.O. or LP. Group 1 mice were administered orally with 50 mg/kg of Compound 20. The remaining mice Groups 2, 3 and 4 were treated via IP with 10 mg/kg Compound 20, 8 mg /kg of Compound 14 and 238mg/kg Compound CHC respectively. The tumor volume was recorded every two days using the formula
  • V - x a x
  • mice were euthanized with C0 2 and tumor masses were isolated and weighed. The inhibition rate was determined using the formula:
  • mice Female BALB/c nude mice weighing ⁇ 20g were taken and 5.0 10 6 WiDr cancer cells were implanted into their right flanks with 1 : 1 mixture of 0.1 mL PBS and matrigel. The mice were arbitrarily chosen by chance and assigned into 7 groups (6 animals/group) and the treatment was started from the same day of the implantation of cancer cells. Mice in group 1 were orally administered two times daily with lOOmg/Kg of Compound 20. Mice in group 2 were orally administered four times per day with 50mg/Kg of Compound 20. Group 3 mice were injected intraperitoneally 2 times per day with lOOmg/Kg of Compound 20.
  • mice were injected intraperitoneally one time per day with lOOmg/Kg and group 5 mice were injected intraperitoneally 2 times per day with 50mg/Kg of Compound 20.
  • Group 6 was treated with 0.2mL of 2% DMSO in water intraperitoneally 4 times daily and group 7 mice were assigned as the control group to which tumor was allowed to grow without any drug administration (food only). The tumor volume was recorded every two days using the formula
  • V - x x Zr
  • mice from group 1, 2, 3, 4 and 6 were euthanized with C0 2 and tumor masses were isolated and weighed.
  • the inhibition rate was determined using the formula:
  • mice from group 5 and 7 were treated with the above mentioned dosage for one more week (21 days) and were euthanized with C0 2 and tumor masses were isolated and weighed. The inhibition rate was determined using the above formula.
  • Example 9 illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.

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Abstract

La présente invention concerne des composés de formule (I) ou un sel de ceux-ci tels que décrits ici. L'invention concerne également des compositions pharmaceutiques contenant un composé de formule (I), des procédés de préparation de composés de formule (I), des intermédiaires utilisables en vue de la préparation de composés de formule (I) et des méthodes thérapeutiques faisant appel auxdits composés de formule (I) et permettant de traiter cancers ou maladies auto-immunes ou, encore, de prévenir le rejet de greffe.
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